tbuckley/cabot-search huggingface dataset:
Evaluating adherence to NCCN guideline-directed genetic screening for patients with pancreatic ductal cell adenocarcinoma in rural northeast Georgia.
Authors: Aditya Kumar Ghosh, Sheena Bhushan, Oluseyi Abidoye, Devi Sampat
Journal: Journal of Clinical Oncology (2023)

e16311 Background: Patients with mutations in BRCA 1/2 genes are at increased risk for pancreatic ductal cell adenocarcinoma (PDAC) in addition to breast and ovarian cancer. In 2019, the NCCN updated its guidelines recommending gene testing for all patients with PDAC to include associated genes: ATM, BRCA1, BRCA2, CDKN2A, MSH2, MLH1, MSH6, EPCAM, PALB2, STK11, TP53. This retrospective, observational study reports on adherence to genetic screening recommendations among patients with newly diagnosed PDAC who received oncologic care in rural Northeast Georgia (NEGA). Methods: Chart abstraction was performed utilizing the EPIC database from hospital electronic medical records of patients who were diagnosed with PDAC between 1/1/20-12/31/21 and received oncologic care in rural NE GA. This abstraction was completed to include information on gene testing recommendations, testing completion, and time from diagnosis to testing. The deidentified dataset was then analyzed using appropriate descriptive and associative statistical testing. Results: Of the cohort of 109 patients diagnosed with PDAC over these two years, only 32 (29.4%) received recommendations and completed genetic screening. Among this segment of patients, 16 (14.7%) were screened within 10 days of diagnosis, 8 (7.3%) within 11-30 days, and 6 (5.5%) were screened over 30 days after being diagnosed with PDAC. Among the 77 (70.6%) patients who did not receive screening, 45 of them (41.3%) did not receive any discussion regarding screening despite planning for other standard of care treatment. The remaining 32 patients (29.4% of the no screening cohort) did not receive screening due to desire to pursue palliative care/hospice/or due to terminal illness that prevented further workup. Of the 45 patients who did not receive screening despite PDAC treatment intent, majority (43; 95.5%) did not receive recommendations regarding the importance of genetic screening. Gene testing of the 32 patients who had screening completed showed that 4 (12.5%) had a pathogenic mutation (3 with CFTR; 1 ATM) and 16 (50%) had variants of unknown significance (VUS). Conclusions: This study highlights a gap in adherence to guideline-directed genetic testing in PDAC patients. Notable findings include increased likelihood to complete the test when recommendations and discussions of genetic screening occurred early in the course after initial diagnosis of PDAC. Moreover, 12.5% of those screened were found to have pathogenic mutation and half were found to have at least one VUS suggesting that genetic screening may potentially identify causative mutations. The findings also highlight the consideration for gene testing recommendation for the large proportion of patients who are terminally ill at diagnosis, as genetic screening would potentially benefit the family members and inform that they receive genetic screening as well.
SpliceIO: A robust platform for the discovery and validation of splicing-derived neoantigens.
Authors: Gayatri Arun, Kendall Anderson, Miguel Angel Manzanares, Sakshi Gera, Hasan Zumrut, Shaleigh Smith, Taylor Floyd, Sanjana Shah, Nayab Habib, Devon Trahan, Martin Akerman
Journal: Journal of Clinical Oncology (2023)

2581 Background: Splicing dysregulation is a major hallmark of cancer, affecting tumor progression, metastasis, and therapy resistance. Aberrant alternative splicing plays a critical role in generating tumor-specific neoantigens targetable through an arsenal of immunotherapeutic modalities. Such neoantigens cannot be discovered using conventional DNA-based tools; they require specialized software for alternative splicing analysis using RNA-seq data. Methods: Envisagenics has developed SpliceIO, a proprietary software platform for splicing-derived neoantigen discovery. SpliceIO uses RNA-seq data to uncover extracellular neoantigens encoded by transmembrane proteins or presented to immune cells through the MHC complex. This predictive ensemble maximizes the value of RNA-seq data to predict fundamental aspects of neoantigen activity, such as their protein localization, MHC binding affinity, epitope accessibility and cancer pathway relevance. Here, we summarize the discovery and validation of novel splicing-derived neoantigens identified using SpliceIO in acute myeloid leukemia and colorectal cancer. Results: We analyzed &gt;10,000 RNA-seq samples from the four tumor types and controls derived from 32 normal tissues. To maximize the prevalence of neoantigen target candidates in patient subpopulations, RNA-seq samples were pre-stratified using SpliceSlice, a proprietary software for spliceosomal profiling. As a result, patients sharing common spliceosome alterations were grouped into 11 coherent subsets that are distinct from normal tissue. Using this approach, we have discovered several promising candidates that we prioritized for experimental validations. SpliceIO target candidates were validated experimentally in cancer cell lines and primary tumor tissues to confirm RNA expression, translation, and membrane localization. Additionally, we performed proteomics to evaluate the presence of neopeptides generated from the unique splicing events. Using this approach, we have discovered and validated several tumor specific splicing derived neoantigens that are also recurrent in &gt;15 % of the population. Conclusions: Together, our results strongly support the role of aberrant splicing as a major source of tumor-specific neoantigens. Our combined computational and experimental approach promotes novel target discovery, enabling the development of novel immunotherapeutics for cancer treatment.
Clinical evaluation of cancer signal origin prediction and diagnostic resolution following multi-cancer early detection testing.
Authors: Eric A. Klein, Charles H. McDonnell, Lincoln Nadauld, Christina A. Dilaveri, Robert Lawrence Reid, Catherine R. Marinac, Karen C. Chung, Margarita Lopatin, Eric T. Fung, Deborah Schrag, Rita Shaknovich
Journal: Journal of Clinical Oncology (2023)

10520 Background: PATHFINDER (NCT04241796) was a prospective, interventional return of results study that enrolled 6,662 participants (pts) from 7 US institutions to assess clinical implementation of a blood-based multi-cancer early detection (MCED) test. Test results for those with a cancer signal detected also included a cancer signal origin prediction designed to help guide diagnostic evaluations. We analyzed whether the diagnostic evaluations in PATHFINDER were appropriately directed by cancer signal origin predictions, assessed the residual risk of cancer after negative initial evaluation, and examined the role of whole-body imaging (WBI, defined as PET/CT or CT chest/abdomen/pelvis) in diagnostic evaluation. Methods: Analysis included pts with a cancer signal detected result from the two different versions of an MCED test evaluated in PATHFINDER. Prespecified criteria blinded to study results were used to define expected diagnostic evaluations by cancer signal origin prediction. These criteria were then used to judge concordance between cancer signal origin predictions and the diagnostic evaluation actually performed. Definitive cancer or no cancer diagnosis (cancer status at end of study [EOS]) was assessed at 12 months after enrollment (EOS). Results: 39 pts had cancer signal detected results by both test versions. Diagnostic evaluations were consistent with cancer signal origin in 30/39 (77%) cases. Diagnostic resolution was achieved in 32/39 (82%) pts after initial evaluation, while 7/39 (18%) required additional workup. 25 of the 32 (78%) pts who achieved diagnostic resolution after initial evaluation had a cancer signal origin-guided workup. Additional evaluation of the 7 pts not achieving initial diagnostic resolution was based on persistent clinical suspicion of cancer due to prior cancer history (n = 1) or abnormal/equivocal findings on initial evaluation (n = 6). Additional workup led to diagnostic resolution in all 7 cases (3 with cancer and 4 with no cancer confirmed at EOS). WBI was ordered in 27 cases, of whom 9 had a prior cancer history, 10 had non-localizing cancer signal origin (hematologic or indeterminate), and 1 had both. WBI was equivocal or had no impact on diagnostic resolution in 8/27 (30%) cases. Conclusions: Most cases resulted in diagnostic resolution after cancer signal origin-directed diagnostic workup. In pts with a cancer history and negative initial evaluations, and those with equivocal initial evaluations, there was still a risk of cancer, suggesting the need for additional evaluation. WBI was used mostly in those with a cancer history or non-localizing cancer signal origins, and had no impact on diagnosis in almost one-third of pts. Clinical trial information: NCT04241796 .
Dupilumab for the treatment of dermatologic adverse events associated with MEK and EGFR inhibitors.
Authors: Stephanie Gu, Stephen W Dusza, Ira J. Dunkel, Alexander E. Drilon, Mario E. Lacouture, Alina Markova
Journal: Journal of Clinical Oncology (2023)

3143 Background: Mitogen activated protein kinase kinase inhibitors (MEKi) and epidermal growth factor receptor inhibitors (EGFRi) are targeted therapies used in the treatment of various cancers. Dermatologic adverse events (dAEs) are common with these medications. Dupilumab, a human monoclonal antibody that targets IL-4, is an FDA approved therapy for the treatment of atopic dermatitis. It has also shown utility in the treatment of many other skin disorders, including toxicities associated with anticancer therapies. In our study, we aim to evaluate the efficacy and safety of dupilumab for the treatment of MEKi/EGFRi associated dAEs. Methods: Patients who received dupilumab for the treatment of a dAE attributed to MEKi or EGFRi from 3/1/2017 to 10/1/2022 were identified at Memorial Sloan Kettering Cancer Center. Severity of dAEs was graded at baseline and follow up using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Patient response to dupilumab was categorized into complete response (CR) (reduction to grade 0), partial response (PR) (reduction to grade 1), or no response (NR) (including change from grade 3/2 to grade ≥ 2). Results: A total of 17 patients (median age 62 years [5 – 87], 58.8% female) who received dupilumab for MEKi (70.6%) or EGFRi (29.4%) related dAEs were identified. Two patients on MEKi were also on concomitant BRAF inhibitors. Patients were white (88.2%), black (5.9%), and Asian (5.9%) and were all undergoing treatment for solid tumors. All dAEs had an eczematous phenotype; 16 were grade 2 (88.2%) and one (5.9%) was grade 3. The median time from dAE development to initiation of dupilumab was 121 days (5 – 1330). Following treatment, 15 patients (88.2%) experienced improvement, with 46.7% and 53.3% achieving CR and PR, respectively. Patients were on dupilumab for a median of 89 days (0-2556), with CR and PR patients exhibiting initial documented response after a median of 30 days (6 – 173). The median CTCAE grade decreased from 2 to 1, and the number of patients on topical and systemic steroids following addition of dupilumab decreased from 17 (100%) to 7 (41.2%) and 5 (29.4%) to 1 (5.9%), respectively. As a result of intolerable anti-cancer therapy-associated dAEs, 4 patients (all on MEKi) initially discontinued their antineoplastics. Three patients (75%) were successfully rechallenged with their original MEKi, while 1 (25%) was switched to another MEKi without subsequent dAE recurrence. No patients reported adverse events to dupilumab treatment. Conclusions: Patients may experience eczematous eruptions while undergoing treatment with MEKi or EGFRi. Dupilumab may be a safe and effective steroid sparing therapeutic option for the management of these dAEs.
PVR expression in tumor microenvironment of advanced hepatocellular carcinoma.
Authors: Li-Chun Lu, Yi-Hsuan Lee, Yu Yun Shao, Tsung-hao Liu, Ann-Lii Cheng, Chih-Hung Hsu
Journal: Journal of Clinical Oncology (2023)

e16113 Abstract Background: PVR (CD155)/TIGIT signaling has been investigated as a new immune checkpoint target in many cancers, including hepatocellular carcinoma (HCC). However, the expression and clinical significance of PVR, the ligand of TIGIT, have not been explored in the tumor microenvironment (TME) of advanced HCC. Methods: Patients with HCC who had adequate tumor tissues obtained at advanced stage were enrolled in the study. The membranous staining of PVR of tumor tissues, detected by immunohistochemistry (IHC), was semiquantitatively scored as IHC 0, 1, 2, or 3 if &lt; 1%, ≥1% but &lt; 5%, ≥5% but &lt; 10%, or ≥10% of tumor cells (TCs) and tumor-infiltrating immune cells (ICs) were PVR positive. The correlation of PVR expressions and other clinic-pathologic factors was analyzed. Results: Sixty-seven patients were included in the study. Among them, 57 (85.1%) were male, 32 (47.8%) were aged over 60 years, 48 (71.6%) were HBV-reactive, and 23 (34.3%) had been treated with sorafenib before obtaining tumor tissues. Thirteen (19.4%) and 18 (26.9%) tumor samples showed positive PVR expressions in TCs and ICs, respectively (TCs, IHC 1/2/3: 3/3/7; ICs, IHC 1/2/3: 7/3/8). The expressions of PVR in TCs or ICs were not associated with sex, age, HBV/HCV infection, previous sorafenib treatment, or overall survival of the patients. Notably, in both TCs and ICs, the intensities of PVR expression were inversely correlated with PD-L1 expression for patients with at least IHC ≥1 in either PVR or PD-L1 (TCs, n = 26, r = -0.6966, p &lt; 0.0001; ICs, n = 46, r = -0.4548, p = 0.0015). Conclusions: PVR expression can be identified in both TCs and ICs of TME of advanced HCC. The expressions of PVR and PD-L1 were inversely correlated. These findings may provide clinical implications for development of combination immunotherapy in advanced HCC. (This work is supported by grants from the Ministry of Science and Technology, Taiwan, MOST 110-2314-B-002-204-MY3). [Table: see text]
Co-occurrence of mutations and related signal pathway analysis of CCND1 amplification in esophageal squamous cell cancer.
Authors: Qingsong Pang, Wencheng Zhang, Tian Zhang, Xi Chen, Fangdong Zhao, Jiacheng Li, Jie Dong, Yang Liu, Qian Wang, Shanshan Xiao, Tao Wang
Journal: Journal of Clinical Oncology (2023)

e16044 Background: Profiling molecular subtypes was usually necessary for cancer patients to facilitate better treatment strategy. Esophageal squamous cell cancer (ESCC) has four subtypes including cell cycle pathway activation (CCA), NRF2 oncogenic activation (NRFA), immune suppression (IS), and immune modulation (IM). CCND1 amplification is one of the important molecular biomarkers for CCA subtype. Previous research showed that CCND1 amplification was associated with immune resistance in ESCC. The co-occurred mutations and related signaling pathways are of great interest to study molecular mechanism in ESCC. Methods: This study enrolled 50 ESCC patient samples comprising 19 whole exome sequencing (WES) samples, 18 whole genome sequencing (WGS) samples and 13 NGS panel (667 genes) samples. To use all the samples, the minimal set of 667 genes was analyzed in detail for gene amplifications and mutations. Kaplan-Meier (KM) survival analysis was applied to study the prognosis associations with the frequently occurred amplifications including CCND1, FGF3, FGF4 and FGF19, etc. Gene expression profiles were then investigated by RNA-Seq sequencing on ESCC cell lines with CCND1 (K30-N) and without CCND1 gene (K30-S, knocked out). PCA analysis was applied to explore the differences between K30-S and K30-N, and KEGG and GO enrichment analysis were performed on the differential expressed genes (DEGs). All analyses were carried out through R4.1.0. Results: The mutational profiles showed that TP53, CCND1, FGF4, FGF19, FGF3, and CDKN2A/B were the most frequently mutated genes in ESCC patients, with the mutation frequencies of 62%, 58%, 56%, 50%, 48% and 40%, respectively. Among those genes, CCND1 and FGF3/4/19 co-occurred amplifications presented in almost all the samples and no other co-existent gene amplifications were identified. The CCND1 and FGF3/4/19 amplification patients were associated with worse prognosis. A total of 1494 differential expressed genes were identified between K30-N and K30-S cell lines, including 998 up-regulated genes and 496 down-regulated gene in K30-S cell line. KEGG enrichment analysis showed that these DEGs were mainly enriched in MAPK signaling pathway, p53 signaling pathway, mTOR signaling pathway and etc. GO enrichment analysis revealed that these differential genes are mainly enriched in cell growth, developmental cell growth, Ras protein signal transmission. Those results were consistent with CCA molecular subtype and highlighted the important role of CCND1 in ESCC subtype classification. Conclusions: This study demonstrated that CCND1 and FGF3/4/19 amplifications frequently co-occurred in ESCC and they were associated with worse prognosis. Signal pathway analysis showed CCND1 play important roles in subtype classification of ESCC.
Women cancer early detection and linkage to care (navigation) in Rwandan community.
Authors: Theoneste Maniragaba
Journal: Journal of Clinical Oncology (2023)

e18740 Background: Whilst early detection and treatment of breast and cervical cancers are increasing, a large number of cancer patients in low and middle income countries lack access to prompt, high-quality diagnosis and care.This study’s primary objective was to demonstrate real time prevalence of breast and cervical cancer from Rwandan district community and establish a link to care for timely diagnosis and treatment in order to curb the health system delays. Methods: From June 2022 January 2023, the Women's Cancer Early Detection Program (WCED) was initiated in Kicukiro district health facilities. The community health workers were Identified, training was given, centers were chosen for integrated screening then clinical breast exams /ultrasound for suspected lesions and cervical cancer screening ((HPV DNA /VIA) done. Precancerous lesions treated by thermal ablation in the community. Patient suspected for cancer were navigated to Rwanda military hospital for biopsy and treatment. Results: A total number of 4,991 were screened. 372 with abnormal findings on clinical breast exam then through ultrasound, 16 women were selected for biopsies. From the highly suspected, 13 (0.3%) confirmed positive for breast cancer. All confirmed cancer cases were staged according to AJCC 8 th edition (TNM) at Rwanda cancer center. TNM staging revealed that 7 (54%) women out of those 13 were of T1-T2N0M0(early stage).They were sent to the multidisciplinary team for treatment planning and treatment with curative intent initiated. Conclusions: Rwanda biomedical center indicates that 65% of our patients arrive at treatment centers with T3-T4N1-3M0-1 (locally advanced and metastatic). The above data shows that through the integrated navigation program, there is a shift from presentation t late stage to early stage. This model is simple and easy for low and middle income countries because it ensures a proper referral process, efficient delivery of optimal care, and patient support to overcome challenges mainly due to health system delay.
Survival trends for left and right sided colon cancer using the population-based SEER database: A 45-year analysis from 1975 to 2019.
Authors: Mark Bilinyi Ulanja, Kwabena Oppong Asafo-Agyei, Bryce D Buetler, Daniel Antwi-Amoabeng, Reginald N. Ulanja, Vijay Neelam, Tarig Mabrouk, Samuel B Governor, Millicent Amankwah, Ganiyu A. Rahman, Francis T. Djankpa, Olatunji B. Alese
Journal: Journal of Clinical Oncology (2023)

e15560 Background: Survival differences between left sided (LCC) and right sided colon cancer (RCC) have been previously reported with mixed results. Many used short study periods and did not account for "other cause of mortality" (OCM). The differences in survival may exist irrespective of modern therapeutic agents, with implications for future clinical trial designs. Methods: We sought to assess the trends in the cause- specific and overall survival of colon cancer based on sidedness, using competing risk analysis. A SEER database from 1975 to 2019 was used.Time interval chosen based on clinical adoption of modern chemotherapy (1975-1989 = period A, 1990-2004 = B, 2005-2019 = C). Cox model was used for overall survival (OS), and Fine-Gray competing risk analysis for cause-specific survival (CSS). Adenocarcinoma were included, and primary rectal cancers excluded. Results: Of the 227,637 colon cancer patients, 50.1% were female and 46.2% RCC. Racial distribution of LCC vs RCC; Black-48.5% vs 51.5%, White-53.1% vs 46.9%, API/AN-63.7% vs 36.3%; p &lt; 0.001. Age ≥ 65 were more likely to have RCC vs LCC (51.4% vs 48.6%), LCC common for age 18-49 (64.6% vs 35.4%), 50-64 (62.3% vs 37.7%), p &lt; 0.00l. Females more likely to have RCC (50.4%vs 41.9%; p &lt; 0.001), and males to have LCC (58.1% vs 49.6%;p &lt; 0.001). Median CSS for LCC and RCC was 19.3 and 16.7 years respectively for 1975-1989 but median CSS for period B and C did not reach during study period. Median OS increased over time for both LCC (A = 5.5 yrs.; B = 7.6yrs and C = 10.5 yrs.) and RCC (4.3, 5.8 and 7.5yrs respectively). CSS was better for LCC than RCC for period C (aHR 0.89; 0.86-0.92; p &lt; 0.001). LCC consistently showed superior OS for all study periods. Stage stratification showed worse CSS for localized and regional LCC in the earlier study periods, but the risk attenuated over time. However, left sided distant disease had superior CSS for all periods. Overall survival was better for LCC irrespective of stage, with gradual improvement over time(table 1). Conclusions: Over the past four decades, LCC has shown superior survival over right sided tumors. Furthermore, prognosis between LCC and RCC became more divergent in favor of LCC with the adoption of modern chemotherapy. Clinical trials for colon cancer should consider sidedness when recruiting patients for intervention. [Table: see text]